Immunometabolism: Macrophage functions in health and metabolic and liver diseases

Since the discovery of macrophages in adipose tissue, many laboratories have focused their effort on understanding the contribution of these immune cells to metabolic diseases. Despite great progress in characterizing obesity as a state of low-grade inflammation, very little is known about the multiple phenotypes and functions of macrophages in metabolic tissues.

The Aouadi research group. Photo: N/A

About our research

The lack of methods to carefully investigate cell-to-cell variability in macrophage phenotype and to manipulate gene expression in a cell-specific manner has delayed answering these crucial questions. Our lab takes advantage of sophisticated methods to investigate macrophage subpopulations and their function in obesity-associated metabolic complications.

    Group leader

    Myriam Aouadi

    PhD, Group leader

    Myriam Aouadi received her PhD in June 2006 from the University of Nice Sophia-Antipolis, France, in the laboratory of Yannick Le Marchand-Brustel. Her worked focussed on the role of MAPK pathways in the commitment of embryonic stem cells in different lineages. She found that p38MAPK is an important player in the early steps of neurogenesis and myogenesis, while it is required for the late stages of adipogenesis. In 2006, Myriam joined the laboratory of Michael Czech at the University of Massachusetts to work on the emerging field of immunometabolism, that investigates the interactions between immune and metabolic cells. During her postdoctoral studies, she developed a method to deliver siRNA specifically to macrophages in vivo. This unique technology allows the study of particular factors expressed by macrophages specifically. In 2009, Myriam became Assistant Professor at the University of Massachusetts and used this novel technology to show that while macrophages in the adipose tissue could be detrimental to insulin sensitivity they could be beneficial as well.

    Myriam Aouadi started her laboratory at the Integrated Cardio-Metabolic Center at the Karolinska institutet in 2015. Her lab investigates the multiple roles and heterogeneity of liver and adipose tissue macrophages in metabolic diseases.

    According to Myriam, team work, curiosity, passion and enthusiasm are important qualities she is looking for and have found in her lab members.

    Group members

    Emelie Barreby

    PhD student

    After obtaining her Master’s degree in Biomedicine at Karolinska Institutet, Emelie joined the lab of Myriam Aouadi in 2015, working as a research technician. Her interest was to gain experience from working in a lab using state of the art techniques such as RNA-sequencing and targeted gene silencing. During this experience, inspired by Myriam and her research group, Emelie decided to pursue a PhD and register for the doctoral program in 2017. Today, her work involves investigating the phenotype of liver macrophages to better understand their role during the pathogenesis of metabolic diseases by using techniques such as flow cytometry, CyTOF and single cell RNA sequencing.

    As part of Emelies doctoral training she also has the benefit of working side-by-side with bioinformaticians in the center to get trained in bioinformatics. In this way, she has had the opportunity to gain knowledge of the whole process from isolating cells and preparing RNA sequencing libraries to actually analyzing the sequencing data herself.

    Laura Levi

    Senior Lab Manager, PhD

    Laura Levi obtained her masters in industrial biotechnology at the University Federico II of Naples. For two years, she worked as a technician at the research center of Novartis Vaccines & Diagnostics in Siena. After that she enrolled in graduate school at Karolinska Institutet; Lauras PhD focused on the connection between chronic infection and cancer development in vitro and in vivo. Laura Levi joined Dr. Aouadi’s lab in January 2016 and since then she has had the opportunity to work in a very dynamic and enthusiastic group that is developing unique and novel strategies to understand metabolic diseases. The goal of the group is to contribute to improving the patients’ quality of life.

    As a Senior Lab Manager, Laura Levi provides technical and scientific support in all the different projects.

    Valerio Azzimato

    Postdoc

    Valerio Azzimato obtained his PhD in Pharmacological Sciences from Università Statale di Milano in 2014. Valerios research project focused on epigenetic mechanisms regulating intracellular communication in cardiovascular scenario. In 2015 he joined Karolinska Institutet as a junior postdoc in order to investigate the interplay between DNA methylation, molecular pathways and metabolism in heart diseases. In February 2018, Valerio joined Dr. Aouadi's group in order to study the role(s) of liver macrophages in the regulation of systemic metabolism. In Myriam's lab he has the opportunity to use state-of-the-art techniques to investigate the crosstalk between immune and metabolic cells. The aim of Valerio Azzimato's research is to better understand the molecular circuits responsible for the development of metabolic diseases.

    Ana Vankova

    Laboratory technician

    After finishing her Bachelor in Chemistry - Analytical Biochemistry, Ana Vankova decided to pursue her passion for medical research. She obtained a Master of Science - Molecular Medicine at the Norwegian University of Science and Technology. During Ana's masters she worked on determining the impact of NEIL3 on neuronal maturation and organization in the hippocampal formation and the medial enthorinal cortex. In June 2020 Ana Vankova joined Dr. Aouadi's lab as a laboratory technitian where she has the opportunity to work in a positive, challenging and collaborative environment. The current goal for Ana is to help with the progress of the lab in understanding the role of the immune system in the development of metabolic diseases while learning and developing her laboratory skills. In the future Ana says that she would like to continue her academic studies in Dr. Aouadi's lab.

    Ping Chen

    Assistant Professor

    As a computational biologist, Ping Chen is keen in translating data science to medical research. Ping Chen obtained her PhD in medicine from University of Helsinki in 2016. Her research was using system biology approaches to study the transcriptome dynamics during the evolution and treatment resistance in cancer. After her PhD, Ping Chen joined Professor Rickard Sandberg’s group as a junior postdoc. Her research projects focused on single cell data analysis and computational method development on various metabolic tissues in collaboration with different metabolic groups from Integrated Cardio-Metabolic Center at Karolinska Institutet. During the collaborations, Ping Chen got very interested in the field of metabolism and was eager to continue her research on metabolic diseases, such as obesity and diabetes. In 2020, Ping Chen joined Dr. Myriam Aouadi’s research group with aims to develop system biology approaches to in-depth understand the molecular mechanisms that drive the transcriptomic dysregulation in human metabolic diseases.

    Sebastian Nock

    Postdoc

    Sebastian Nock obtained his PhD in 2020 from the University of Lübeck where he identified new biomarkers for thyroid hormone disorders in a translational approach. In this context he investigated the role of thyroid hormones and their contribution to the functions of liver-resident macrophages. Sebastian Nock joined the group of Myriam Aouadi, to identify and characterize macrophage populations that are involved in the progression of obesity-induced comorbidities in the liver and decipher underlying mechanisms to contribute to prospective therapeutic approaches. In this group Sebastian Nock has the possibility to draw on experience with state-of-the-art technologies like single cell RNA sequencing, liver spheroids and sophisticated bioinformatic tools. The group also provides the tight connection of clinical and pre-clinical trials that allows Sebastian to directly translate findings into the clinical context.

    Achilleas Fardellas

    PhD Student

     Achilleas Fardellas obtained the M.Pharm. at the University of Patras and M.Sc. in Toxicology at Karolinska Institutet before joining the R&D Graduate programme at AstraZeneca - a two-year talent programme comprised of three different eight-month placements across the R&D organisation. Throughout his academic and industrial experience, his main research focus has been how we can employ human relevant in vitro systems such as 3D liver organoids, as well as system biology approaches to model and decipher the complex pathophysiology behind metabolic diseases.  Achilleas Fardellas joined Dr. Aouadi’s multi-cultural and inspiring group in October 2020 to pursue his doctoral studies.  Achilleas Fardella's ambition in the group is to dissect how RNA editing processes in macrophages regulate insulin resistance and contribute to NASH progression by combining state-of-the-art in vitro, in vivo and in silico techniques.

    Madara Brice

    Research assistant

    Madara Brice obtained her Bachelors degree in Biomedical Sciences at the University of Edinburgh in 2019. During her undergraduate thesis, she investigated two potential anti-fibrotic agents and their effect on human hepatic stellate cells in vitro. After graduating, Madara wanted to continue gaining experience in academic research, so she joined Prof. Neil Henderson’s lab at the Centre for Inflammation Research at the University of Edinburgh as a research assistant. During her time there, Madara gained valuable technical and scientific experience and furthered her interest in liver research. She joined Dr. Aouadi’s group in August 2021 as a lab technician, to work on various exciting ongoing projects, all centered around the role of macrophages in metabolic diseases. Madara is looking forward to gaining more laboratory and scientific experience in a different environment, whilst helping progress the lab’s projects. In the future, she hopes to begin her PhD studies in a lab in Sweden.

    Léa Naudet

    Research assistant

    Léa Naudet obtained her Bachelor’s double diploma in Human and Molecular Biology from the Universities of Strasbourg, France and Saarbrücken, Germany in 2019. During her Bachelor’s thesis, her interest in diabetes and obesity led her to investigate the role of oxidative stress in pancreatic beta-cell signaling, dysfunction and death. Wanting to make a difference in translational research, she enrolled in Karolinska Institutet’s Master’s Programme in Biomedicine and graduated in 2021 with a specialization in metabolic and cardiovascular diseases. Léa joined Myriam Aouadi’s lab during her degree project, during which she was supervised by Emelie Barreby and focused on elucidating the zonation of liver macrophage populations previously identified by single-cell RNA seq and their fate in the context of obesity.  

    Inspired by Myriam Aouadi and her team and motivated to contribute to her colleagues’ research projects, she decided to continue working in the Aouadi lab as a research assistant. There, she has the chance to learn state of the art techniques in a highly dynamic, cooperative and international environment and to improve her knowledge in metabolic diseases and immunometabolism. In the future, Léa says she would like to pursue her goals of improving the translational understanding of obesity and diabetes by continuing her academic studies as a Ph.D. student in Myriam Aouadi’s lab. 

    Previous group members

    Cecilia Morgantini, MD, PhD, former postdoctoral fellow, now Team Leader at the Cardiometabolic Unit (CMU) at Karolinska Institutet.

    Marcela Aparicio-Vergara, PhD, former postdoctoral fellow, now research manager of Nutrition & Health at NutriLeads, Netherlands.

    Francisco Verdeguer, PhD, former postdoctoral fellow, now group leader at the University of Zurich.

    Jennifer Jagger PhD, former postdoctoral fellow, now Principal investigator at the University of Nice, France.

    Joost Willebrords PhD, former postdoctoral fellow, now R&D and Innovation Consultant at Leyton, Belgium.

    Connie Xu, former research assistant, now molecular biologist at CareDx, Inc. Stockholm, Sweden.

    André Sulen PhD, former postodoctoral fellow, now postodoctoral fellow at the University of Bergen, Norway.

    Projects

    Study the mechanism whereby factors produced by liver macrophages regulate insulin sensitivity.

    We have recently discovered that mice fed a high fat diet (HFD) become rapidly obese and insulin resistant independently of liver inflammation, which was thought to be an important driver in obesity-induced insulin resistance. On the other hand, depletion studies have shown that removing liver macrophages (LMs) prevents insulin resistance induced by obesity, suggesting an important role of LMs in the regulation of insulin sensitivity. Using RNAseq, we identified genes specifically expressed by liver macrophages, whose expression significantly increases with obesity and insulin resistance. We then took advantage of a powerful and unique tool, called glucan encapsulated RNAi particles (GeRP), that deliver siRNA and silence genes specifically in macrophages in vivo.

    This technology is based on small interfering RNA (siRNA) encapsulated within glucan particles derived from baker’s yeast. By using intraperitoneal injections, we showed that GeRPs delivered siRNA and silenced genes specifically in macrophages in the adipose tissue of obese mice. However, by using intravenous administration, we showed that GeRPs delivered siRNA and silenced genes in LMs but not in hepatocytes or macrophages within other tissues.

    Using this unique method, we found that silencing genes of interest specifically in LMs improves insulin sensitivity in obese mice. This project has so far confirmed that liver macrophages can play a role in the regulation of insulin sensitivity independently of inflammation. This opened a new avenue towards the discovery of the multiple roles of immune cells other than only the inflammatory response.

    Identify distinct phenotypes and functions of macrophages in liver and adipose tissue.

    Macrophages are able to modulate their properties upon contact with different cell types as well as extracellular matrix. Their intrinsic heterogeneity during differentiation is compounded by reciprocal interactions with neighbouring cells, including other macrophages. In many different tissues, macrophages can occupy different anatomical niches and perform specialized functions even within the same organ. Emerging data suggest that macrophages acquire specialized functions, which are tailored for assisting local homeostasis, within each particular organ.

    We use scRNAseq, metabolomics, flow cytometry, CytOF and in situ transcriptomic to study the heterogeneity of resident macrophage in liver and adipose tissue in health and metabolic disease.

    Decoding the phenotype of macrophages through the study of non-coding RNA

    We aim at identifying dysregulated genes but also non-coding RNAs such as microRNAs, enhancer RNAs, and long non-coding RNAs which have recently emerged as important regulators of gene expression, and which expression have been associated with several diseases. Using the Global Run-On sequencing (GRO-seq) to directly measure rates of nascent transcription genome-wide, we propose to identify all transcript, genes and non-coding RNAs dysregulated in LMs in obesity that could be involved in the development of insulin resistance.

    We are especially interested in enhancers, which are regions of DNA important for the regulation of genes transcription, and can be transcribed as non-coding RNAs called enhancer-derived RNAs (eRNAs). The eRNAs can regulate the expression of the nearby gene, and have also been shown to be superior markers for active enhancers because of their small size and high dynamic ranges. The mining of the GRO-seq data for eRNAs transcription to map functional enhancers, combined with genome-wide de novo motif analysis performed at sites of eRNAs dysregulation in LMs from obese and insulin resistant mice compared to lean mice, will allow us to identify the transcription factor(s) that could be involved in gene dysregulation in LMs in obesity.

      Research support

      • Integrated Cardio Metabolic Center/Astrazeneca start-up fund (2015-2020).
      • Swedish Research Council project grant (2020-2025).
      • SRP Diabetes at Karolinska Institutet (2018-2020).
      • Novonordisk Foundation through the Tripartite Immuno-metabolism Consortium (2016-2020).
      • Novonordisk Foundation project grant and exploratory pre-seed grant (2019-2020)
      • Karolinska Institutet consolidator grant (2020-2025)
      • European Research Council consolidator grant (2020-2025)
      • European Research Council

      Young Investigator in Diabetes Award

      Selected publications

      Liver macrophages regulate systemic metabolism through non-inflammatory factors
      Nature Metabolism Published: 25 March 2019

      Macrophage heterogeneity and energy metabolism.
      Verdeguer F, Aouadi M
      Exp. Cell Res. 2017 11;360(1):35-40

      Liver innate immune cells and insulin resistance: the multiple facets of Kupffer cells.
      Jager J, Aparicio-Vergara M, Aouadi M
      J. Intern. Med. 2016 08;280(2):209-20

      Lipid storage by adipose tissue macrophages regulates systemic glucose tolerance.
      Aouadi M, Vangala P, Yawe JC, Tencerova M, Nicoloro SM, Cohen JL, et al
      Am. J. Physiol. Endocrinol. Metab. 2014 Aug;307(4):E374-83

      Local proliferation of macrophages contributes to obesity-associated adipose tissue inflammation.
      Amano SU, Cohen JL, Vangala P, Tencerova M, Nicoloro SM, Yawe JC, et al
      Cell Metab. 2014 Jan;19(1):162-171

      Activation of the Nlrp3 inflammasome in infiltrating macrophages by endocannabinoids mediates beta cell loss in type 2 diabetes.
      Jourdan T, Godlewski G, Cinar R, Bertola A, Szanda G, Liu J, et al
      Nat. Med. 2013 Sep;19(9):1132-40

      Gene silencing in adipose tissue macrophages regulates whole-body metabolism in obese mice.
      Aouadi M, Tencerova M, Vangala P, Yawe JC, Nicoloro SM, Amano SU, et al
      Proc. Natl. Acad. Sci. U.S.A. 2013 May;110(20):8278-83

      Insulin signalling mechanisms for triacylglycerol storage.
      Czech MP, Tencerova M, Pedersen DJ, Aouadi M
      Diabetologia 2013 May;56(5):949-64

      Glucan particles for selective delivery of siRNA to phagocytic cells in mice.
      Tesz GJ, Aouadi M, Prot M, Nicoloro SM, Boutet E, Amano SU, et al
      Biochem. J. 2011 Jun;436(2):351-62

      Coronin 2A mediates actin-dependent de-repression of inflammatory response genes.
      Huang W, Ghisletti S, Saijo K, Gandhi M, Aouadi M, Tesz GJ, et al
      Nature 2011 Feb;470(7334):414-8

      RNAi-based therapeutic strategies for metabolic disease.
      Czech MP, Aouadi M, Tesz GJ
      Nat Rev Endocrinol 2011 Apr;7(8):473-84

      Orally delivered siRNA targeting macrophage Map4k4 suppresses systemic inflammation.
      Aouadi M, Tesz GJ, Nicoloro SM, Wang M, Chouinard M, Soto E, et al
      Nature 2009 Apr;458(7242):1180-4